The inherited human deficiencies of adenosine deaminase and of purine nucleoside phosphorylase are associated with specific immunological dysfunctions. To understand the molecular pathophysiology and unique immunologic specificities in vivo and to test in vivo therapeutic hypotheses for these two diseases, we plan to generate chimeric mice containing tissues deficient in these specific enzymes. Mouse blastocysts will be injected with mutant mouse embryonal carcinoma (teratocarcinoma) cells isolated in vitro and the immunologic function of the enzyme deficient cells in the chimeric animal will then be analyzed. We have obtained through a collaborative screening program in Leicester, England a stock of mice, derived from a single feral male mouse, heterozygous for purine nucleoside phosphorylase deficiency. From these carriers we expect to generate mice homozygous for purine nucleoside phosphorylase deficiency. These animals will then be examined by the use of biochemical genetics and immunologic chimerism to determine the pathogenic roles of nucleoside phosphorylating enzymes and ribonucleotide reductase in the specific enzyme deficient immunodeficiency diseases. These studies should provide knowledge directly applicable to the management of humans with autoimmune diseases, transplanted organs and lymphoid malignancies.